HIV- 1 -specific CTL responses arise early during the course of infection, and persist at high frequencies, yet do not, in general, control HIV viremia. Although much is known about the magnitude of CTL responses to HIV epitopes comparatively little is known about the diversity of the TCR repertoire to immunodominant epitopes and how the breadth and avidity of this repertoire influences subsequent viremia. Over the previous funding period of this grant we have identified immunodominant CTL responses restricted by several HLA alleles, and have demonstrated that individual clonal CTL responses are able to persist in the host for prolonged periods. We have more recently combined our expertise in sequencing TCR genes with the ability to sort live, antigen-specific populations of CTL to assess the breadth of TCR repertoires to viral epitopes. We propose to determine whether the prompt generation of CTL with diverse TCR repertoires to dominant epitopes is associated with subsequent control of viremia in the absence of HAART. A diverse CTL repertoire is either more likely to cross-react with potential HIV- 1 variants, or is more likely to contain high-avidity CTL clones that are able to effectively suppress viral replication, in each case limiting the ability of HIV-1 to escape immune recognition. These studies will allow us to determine the relationship between the evolution of the TCR repertoire and immune control of viremia. Specifically we propose to: 1) Determine whether the TCR repertoires of immunodominant CTL responses in long-term nonprogressors are narrow due to the long-term selection of dominant clonal populations, or whether they are broad, thus limiting the potential generation of HIV-1 escape variants. 2) Determine whether the initial generation and maintenance of a diverse TCR repertoire is associated with control of viremia in subjects treated early after presentation with an acute retroviral syndrome. 3) Determine whether the generation of a diverse TCR repertoire contains cross-reactive CTL able to recognize potential HIV-1 escape variants. 4) Determine whether the generation of a diverse TCR repertoire contains populations of high-avidity CTL that come to dominate the population of CTL during chronic infection and mediate control of HIV- 1 replication.